TXNRD1: A Key Regulator Involved in the Ferroptosis of CML Cells Induced by Cysteine Depletion In Vitro

Shuhan Liu,Wei Wu,Yan Xue,Donghong Lin,Qiaoqian Chen,Xiandong Jiang,Zhiyuan Zheng,Daniela Giustarini

doi:10.1155/2021/7674565

Shuhan Liu, Wei Wu + Show 6 more

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https://doi.org/10.1155/2021/7674565

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Abstract

Cysteine metabolism plays a critical role in cancer cell survival. Cysteine depletion was reported to inhibit tumor growth and induce pancreatic cancer cell ferroptosis. Nevertheless, the effect of cysteine depletion in chronic myeloid leukemia (CML) remains to be explored. In this work, we showed that cysteine depletion can induce K562/G01 but not K562 cell death in the form of ferroptosis. However, the glutathione (GSH)/glutathione peroxidase 4 (GPX4) pathways of the two CML cell lines were both blocked after cysteine depletion. This unexpected outcome guided us to perform RNA-Seq to screen the key genes that affect the sensitivity of CML cells to cysteine depletion. Excitingly, thioredoxin reductase 1 (TXNRD1), which related to cell redox metabolism, was significantly upregulated in K562/G01 cells after cysteine depletion. We further inferred that the upregulation is negatively feedback by the enzyme activity decrease of TXNRD1. Then, we triggered the ferroptosis by applying TXNRD1 shRNA and TXNRD1 inhibitor auranofin in K562 cells after cysteine depletion. In summary, we have reason to believe that TXNRD1 is a key regulator involved in the ferroptosis of CML cells induced by cysteine depletion in vitro. These findings highlight that cysteine depletion serves as a potential therapeutic strategy for overcoming chemotherapy resistance CML.

Highlights

Chronic myeloid leukemia (CML) is a hematopoietic stem cell disease [1]
We demonstrated that thioredoxin reductase 1 (TXNRD1) may be a key gene involved in the regulation of ferroptosis in CML cells
MTS showed that the cell viability of K562/G01 was decreased after cysteine depletion compared with normal culture condition, while there is no change in K562 cells (Figure 1, P < 0:001)

Summary

Introduction

Chronic myeloid leukemia (CML) is a hematopoietic stem cell disease [1]. Tyrosine kinase inhibitor imatinib can improve the prognostic survival rate of most CML patients, there are still many problems that hinder the therapeutic effect of CML, such as drug side effect and drug resistance [2,3,4]. It is urgent to explore new strategies to overcome CML treatment bottleneck. Targeting cysteine metabolism is considered as a new potential therapy for cancers [5,6,7]. Research indicates that synthetic cysteine enzyme can decompose cysteine in the blood to suppress the tumor growth in breast and prostate cancer xenografts without obvious toxicity on normal cells [8]. It is speculated that targeting cysteine metabolic has broad application prospects

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